Inflammation and regulation have opposing effects on the induction of transplant tolerance. We recently discovered that OX40 is at the apex of both processes. OX40 blocks the induction of proinflammatory Th17 cells, which is an important tolerogenic feature in transplant models, but it also blocks the induction of Foxp3+ Tregs from na[unreadable]ve T effector cells, which is detrimental to allograft tolerance. Understanding precisely the molecular pathways utilized by OX40 to turn off both Foxp3+ Tregs and Th17 cells in the periphery and to determine whether such pathways can be manipulate to selectively rescue the induction of Foxp3+ Tregs for the purpose of tolerance induction is the central focus of this project. We hypothesized that OX40 costimulation to T effector cells initiates diverse signaling pathways that are differentially involved in suppressing the induction of Foxp3+ Tregs and proinflammatory Th17 cells, and by selectively modulating such signaling pathways, the effect of OX40 on Tregs and Th17 cells can be segregated in such a way that induction of cytopathic Th17 cells remains inhibited by OX40 but generation of Foxp3+ Tregs is unperturbed. We have proposed a series of comprehensive experiments in this proposal that covers all aspects of OX40 costimulation. We focused specifically on the immediate signaling events of OX40 and those that impact on the effector programs of naove T cells as well as the therapeutic implications in tolerance induction. We believe that the significance of this project is likely to be two folds;as viewed from a basic science vintage point, accomplishment of proposed studies will provide seminal insights on how a single cell surface costimulatory molecule regulates the effector and the regulatory programs of na[unreadable]ve T cells upon activation. From a therapeutic point of view, this proposal may eventually leads to the design of new tolerizing protocols involving stimulating OX40 in the induction of transplant tolerance. All of which are significant issues in transplant immunology. Thus, these studies will provide key insights on the development of new therapeutic strategies aimed at manipulating the Foxp3+ Treg-Th17 pathway in the induction of transplant tolerance as well as in th treatment of autoimmune diseases and cancer. PUBLIC HEALTH RELEVANCE: Organ transplantation is the preferred choice of treatment for end-stage organ failures, but transplant patients must take immunosuppressive drugs for life. The unwanted side effects frequently seen with current immunosuppressive drugs and our inability to control chronic graft loss despite maximal immunosuppression are the compelling reasons for the development of better and more specific tolerance- inducing strategies. Our project is specifically designed to address the issue of inflammation and regulation in transplant settings and whether such responses can be modulated for the induction of donor specific tolerance. Moreover, knowledge gained from those studies will have broad impact on therapeutic interventions of autoimmune disorders and cancer therapies.